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THE NATIONAL ACADEMIES PRESS • 500 Fifth Street, N.W. • Washington, DC 20001
NOTICE: The project that is the subject of this report was approved by the Governing
Board of the National Research Council, whose members are drawn from the councils of
the National Academy of Sciences, the National Academy of Engineering, and the Institute
of Medicine. The members of the committee responsible for the report were chosen for their
special competences and with regard for appropriate balance.
This study was supported by Contract No. N01-OD-4-2139, TO # 215 between the National
Academy of Sciences and the National Institutes of Health. Additional support was provided by
the Food and Drug Administration. Any opinions, findings, conclusions, or recommendations
expressed in this publication are those of the authors and do not necessarily reflect the view
of the organizations or agencies that provided support for the project.
International Standard Book Number-13: 978-0-309-15806-0
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Additional copies of this report are available from the National Academies Press, 500 Fifth
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Copyright 2010 by the National Academy of Sciences. All rights reserved.
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The serpent has been a symbol of long life, healing, and knowledge among almost all cultures
and religions since the beginning of recorded history. The serpent adopted as a logotype by
the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche
Museen in Berlin.
Front cover photographs (top to bottom):
Using electropheresis apparatus to separate proteins by molecular weight.
Photo courtesy of National Institute of Arthritis and Musculoskeletal and Skin Diseases.
96-well, 384-well, and 1,536-well plates used in pharmaceutical and life science research.
Photo courtesy of National Human Genome Research Institute.
Children with ectodermal dysplasia. Used with permission. Photo courtesy of the National
Foundation for Ectodermal Dysplasias.
Image of chromosomal abnormalities in mouse cells from a study of leukemia-promoting
effects of tumor necrosis factor-alpha in Fanconi anemia group C stem cells. Photo courtesy
of the laboratory of Dr. Qishen Pang at Cincinnati Children’s Hospital Medical Center. U.S.A.
Copyright 2007, American Society for Clinical Investigation. Used with permission.
Friedreich’s ataxia patient and Friedreich’s Ataxia Research Alliance (FARA) spokeperson,
Kyle Bryant, on his recumbent trike during the cycling competition Race Across America.
Copyright 2010, www.SLOtography.com. Used with permission.
Children with sickle cell disease. Used with permission. Photo courtesy of Cincinnati Children’s
Hospital Medical Center.
Suggested citation: IOM (Institute of Medicine). 2010. Rare Diseases and Orphan Products:
Accelerating Research and Development. Washington, DC: The National Academies Press.

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“Knowing is not enough; we must apply.
Willing is not enough; we must do.”
— Goethe
Advising the Nation. Improving Health.

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of distinguished scholars engaged in scientific and engineering research, dedicated to
the furtherance of science and technology and to their use for the general welfare.
Upon the authority of the charter granted to it by the Congress in 1863, the Acad-
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and technical matters. Dr. Ralph J. Cicerone is president of the National Academy
of Sciences.
The National Academy of Engineering was established in 1964, under the charter
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sharing with the National Academy of Sciences the responsibility for advising the
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and recognizes the superior achievements of engineers. Dr. Charles M. Vest is presi-
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of the National Research Council.
www.national-academies.org

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Acknowledgments
In preparing this report, the committee and project staff benefited
greatly from the assistance and expertise of many individuals and groups.
Important information and insights came from three public meetings that
the committee organized to collect information and perspectives from a
range of academic, professional, consumer, patient, and other organiza-
tions and individuals. A number of speakers at these meetings also shared
their knowledge at other times during the course of the study. Appendix A
includes the agendas of the public meetings and a list of organizations that
submitted written statements of views. The committee appreciates the con-
tributions of Aaron Kesselheim, author of Appendix B, and Laura Brooks
Faden, coauthor of Appendix C.
Our project officer at the National Institutes of Health (NIH), Stephen
Groft, was an invaluable resource and unfailingly helpful. We also were
advised by others at NIH including Stephen Hirschfield (National Institute
for Child Health and Human Development) and Jeffrey Abrams and Isis
Mikhail (National Cancer Institute). Our project officer at the Food and
Drug Administration (FDA), Timothy Coté, likewise was a great help, pa-
tiently answering questions about the workings of the Orphan Drug Act
and its results. We also were assisted by other FDA staff, particularly Debra
Lewis and Anne Pariser as well as Kui Xu, Menfo Imoisili, and Katherine
Needleman. Joan Sokolovsky at the Medicare Payment Advisory Com-
mission helped with questions about drug coverage under Medicare Parts
B and D. Scott Grosse at the Centers for Disease Control and Prevention
offered useful insights into the complexities of epidemiologic research on
rare conditions.
vii

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viii ACKNOWLEDGMENTS
Sharon Terry and colleagues at the Genetic Alliance and Peter Saltonstall,
Mary Dunkle, and colleagues at the National Organization for Rare Dis-
eases worked with the committee on an invitation for their members to
submit statements of views on issues before the committee. At Orphanet,
Seygolene Ayme provided important information and guidance about their
information resources. A number of individuals in other organizations were
also helpful in a variety of ways. In addition to those who made presenta-
tions during committee meetings and with whom we talked at other meet-
ings, among those we consulted were Stephen Bajardi and Anthony Horton
(International Rett Syndrome Foundation), Ron Bartek (Freidriech’s Ataxia
Research Alliance), Robert Beall (Cystic Fibrosis Foundation), Wendy Book
(American Partnership for Eosinophilic Disorders), Amy Hewitt (Sclero-
derma Research Foundation), Cynthia Joyce (Spinal Muscular Atrophy
Association), Jill Raleigh (LAM [Lymphangioleiomyomatosis] Foundation),
Jodi Edgar Reinhardt (National Foundation for Ectodermal Dysplasias),
and John Walsh (Alpha-1 Foundation). We also called on Carl Whalen
at the National Disease Research Interchange; Yann Le Cam (Eurodis);
Marty Liggett, Ulvana Desiderio, and Stephanie Kart (American Society
of Hematology); Qishen Pang, Vicky Klensch, and Kori Siroky (Cincinnati
Children’s Hospital Medical Center); and Enrique Seoane-Vazquez (Ohio
State University).
In addition, the committee and project staff appreciate the work of copy
editor Florence Poillon; Debra Gilliam, Chanda Chay, and John Bowers of
Caset Associates; and temporary research assistant Cassandra Fletcher.
Within the National Academies, we particularly acknowledge the assistance
of Clyde Behney, Adam Berger, Robert Giffin (now at the Center for Medi-
cal Technology Policy), Greta Gorman, Christine Micheel, Amy Packman,
Donna Randall, and Vilija Teel.

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Reviewers
This report has been reviewed in draft form by individuals chosen
for their diverse perspectives and technical expertise, in accordance with
procedures approved by the National Research Council’s Report Review
Committee. The purpose of this independent review is to provide candid
and critical comments that will assist the institution in making its published
reports as sound as possible and to ensure that the report meets institutional
standards for objectivity, evidence, and responsiveness to the study charge.
The review comments and draft manuscript remain confidential to protect
the integrity of the deliberative process. We wish to thank the following
individuals for their review of this report:
Ronald J. Bartek, Friedreich’s Ataxia Research Alliance
Edward M. Basile, King & Spalding
Jim Burns, Genzyme Corporation
David Frohnmayer, Fanconi Anemia Research Fund
Elaine Gallin, Doris Duke Charitable Foundation
Robert C. Griggs, University of Rochester School of Medicine
Susan Kelley, Multiple Myeloma Research Consortium
Chaitan Khosla, Stanford University
Michael Knowles, University of North Carolina at Chapel Hill
Roger J. Lewis, University of California, Los Angeles
John Linehan, Stanford University
Dawn S. Milliner, Mayo Clinic
Carol Mimura, University of California, Berkeley
John A. Parrish, Massachusetts General Hospital
ix

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x REVIEWERS
Reed E. Pyeritz, University of Pennsylvania
Joan Sokolovsky, Medicare Payment Advisory Committee
Jess G. Thoene, University of Michigan
Although the reviewers listed above have provided many constructive
comments and suggestions, they were not asked to endorse the conclusions
or recommendations, nor did they see the final draft of the report before
its release. The review of this report was overseen by Neal A. Vanselow
and Floyd E. Bloom, Scripps Research Institute. Appointed by the National
Research Council and the Institute of Medicine, these individuals were
responsible for making certain that an independent examination of this
report was carried out in accordance with the institutional procedures and
that all review comments were carefully considered. Responsibility for the
final content of this report rests entirely with the authoring committee and
the institution.

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Preface
Rare diseases are not rare, at least in aggregate. Approximately 7,000
rare diseases afflict millions of individuals in the United States and are re-
sponsible for untold losses in terms of physical health, behavioral health,
and socioeconomic condition. Physicians, nurses, and others who care for
this group of patients recognize the huge burden on patients, families, com-
munities, the health care system, and the health care financing system. All
too frequently, providers are reminded of the gap between patient needs and
our inability individually and collectively to meet those needs.
Although rare diseases taken together have an enormous impact, there
has been no “war on rare diseases” and no designation of a National
Institutes of Health (NIH) institute (as for cancer) to address research on
rare diseases, even though some U.S. prevalence figures for all rare diseases
fall in the range of estimates of those with a history of a cancer diagnosis.
Although neither of these cancer-specific responses to need may be suited to
rare diseases, many patients with rare diseases today have difficulty in find-
ing providers with the expertise and resources to diagnose and treat their
conditions. In addition, research progress has suffered from segmented,
disorder-specific approaches to projects and their funding.
The Institute of Medicine committee was asked to examine the cur-
rent state of research on health care for rare diseases and products to
better prevent, diagnose, and treat the large number of these diseases. The
committee also was charged to consider how the development of research
and therapeutics might be fostered. This task proved to be daunting in a
number of respects. Each rare disease has its particular unmet needs, and
these may not even have been documented for hundreds if not thousands
xi

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xii PREFACE
of extremely rare conditions. Relatively few efforts have successfully ad-
dressed scientific or technical questions across a spectrum of rare diseases.
Furthermore, incentives for pharmaceutical, biotechnology, and medical
device companies, starting with the Orphan Drug Act in 1983, to invest in
the development of new diagnostics, therapeutics, and preventive interven-
tions for rare diseases have had a limited impact on the gap between needs
and effective responses.
As documented in this report, opportunities now exist to accelerate
progress toward understanding the basis for many more rare diseases and
for developing innovative medical approaches. For example, the genomic
era some 20 years ago promised when it was launched to unravel the mys-
teries of genetic contributions to disease. Estimates that 80 percent or more
of rare diseases have a genetic cause provided hope for many that solutions
to their health problems might be around the corner. However, much of the
initial effort to understand the genetic basis of disease was understandably
focused on more common problems. It has, however, become increasingly
evident that many common diseases have a very complex genetic basis that
is taking much longer to map than was originally expected. Because many
rare conditions stem from defects in a single gene, they offer opportunities
for faster progress, especially given scientific and technological advances
that identify the genetic basis of rare diseases and find molecular targets for
the development of new treatments for these diseases. Thus, we are poised
to make rapid advances in the understanding and, in an increasing number
of cases, the treatment of rare diseases. As past research has demonstrated,
some of these advances will undoubtedly illuminate disease mechanisms
and treatment avenues for more common conditions.
At the same time, many obstacles still complicate efforts to accelerate
rare diseases research and product development. Regulatory efforts to ensure
the safety and efficacy of new products for rare diseases need attention so
that they do not impose avoidable delays or apply inappropriate standards
in the evaluation of products for rare conditions. Funding for research for
many rare diseases has lagged and lacked coordination, and investigators
interested in pursuing research on rare diseases face many obstacles related
not just to the availability of funding but to the mechanisms under which
research grants are awarded. Furthermore, the cost of drug development
under current models and the high costs of new drugs for rare conditions
raise questions about whether it is time to create alternative pathways for
drug development, including public-private partnerships.
For these reasons, the committee came to the conclusion that a more
coordinated national, and ideally global, effort to plan and begin system-
atically to implement new strategies for addressing the needs of patients
with rare diseases is a timely consideration. Leadership of this planning
and implementation effort, as well as mechanisms to sustain the effort

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xiii
PREFACE
over time, present formidable challenges but are not insurmountable with
the commitment of patients and families, advocacy groups, policy makers,
companies, investigators, and others. The committee is hopeful that its
efforts will catalyze thought and action that will benefit millions of our
citizens with rare diseases and thereby contribute to the overall health of
the nation.
As chair of the committee, I acknowledge the strong contributions of
two groups. The committee members quickly created an effective team and
gave generously of their time and expertise for committee meetings, phone
calls, and writing and review assignments. The Institute of Medicine staff
brought together the myriad and disparate inputs and assembled them in a
lengthy and complex report. The report would not have materialized with-
out the persistent gentle prodding and guidance of our study director, Dr.
Marilyn Field. Without her insistence on documentation of report elements
to ensure that the report’s content and presentation met the highest stan-
dards under a very ambitious time line, the multifaceted and interdependent
dimensions of the committee’s charge could not have been so thoughtfully
addressed.
Thomas F. Boat, Chair
Committee on Accelerating
Rare Diseases Research and
Orphan Product Development

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Boxes, Figures, and Tables
BOXES
S-1 Elements of an Integrated National Strategy to Accelerate
Research and Product Development for Rare Diseases, 3
1-1 Examples of Rare Diseases, 17
1-2 Elements of an Integrated National Strategy to Accelerate
Research and Product Development for Rare Diseases, 18
1-3 Organized Research on Exceptionally Rare Diseases
Is Possible, 22
1-4 Examples of Ongoing Reporting of New Rare Syndromes in
Orphanet Newsletter, 35
1-5 Rare by Genotype or Rare by Phenotype: The Example of
Hemochromatosis, 36
1-6 Types of Clinical Trials, 39
3-1 Options for Patients to Obtain Access to Investigational Drugs
When the Primary Purpose Is to Diagnose, Monitor, or Treat a
Patient’s Disease or Condition, 80
3-2 Primary Incentives Provided by the Orphan Drug Act, 87
3-3 Examples of Variations in Types of Efficacy Studies Accepted by
FDA in Orphan Drug Approvals, 96
3-4 Examples of Problem Areas for Sponsors Developing Evidence
for Orphan Drug Approval, 99
3-5 NIH Request for Applications on Advancing Regulatory Science
Through Novel Research and Science-Based Technologies (Febru-
ary 24, 2010), 103
xix

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xx BOXES, FIGURES, AND TABLES
4-1 Examples of Research on Rare Diseases with Implications for
Treatment of Common Conditions, 113
4-2 Improving Rare Disease Diagnostics: Enabling Technologies, 124
5-1 Summary of Earlier IOM Report Recommendations for Effective
Biomarker Evaluation, 158
5-2 Examples of Initiatives to Increase Information About Clinical
Trials and FDA or Company Decisions About Products, 166
7-1 Examples of Devices Approved Under the Humanitarian Device
Exemption, 221
7-2 Expectations for Consortia to Stimulate Pediatric Device Devel-
opment, 223
7-3 Stanford University Biodesign Program, 230
7-4 Innovations in Engineering and Biological Sciences and Medical
Device Innovation, 232
FIGURES
2-1A Number of rare diseases by prevalence up to 50/100,000, 49
2-1B Number of rare diseases by prevalence of 10/100,000 or less, 49
2-1C Number of rare diseases by number of individual cases in
literature, 50
2-1D Number of rare diseases by number of family cases in literature, 50
4-1 Plot of NIH grants for illustrative rare diseases by disease preva-
lence, 131
5-1 Drug development: from idea to market, 148
7-1 Total product life cycle for medical devices, 227
B-1 Annual orphan drug approvals by “newness,” 304
TABLES
1-1 Time Line of Selected Events Relevant to Policies Promot-
ing Research and Development for Rare Diseases and Orphan
Products, 24
1-2 Funding for Biomedical Research in the United States by Source,
2007, 28
1-3 Comparison of Selected National Policy Incentives for Orphan
Drug Development, 30